Candidate: My career goal is to become an independent physician-scientist with a primary focus on research aimed at understanding the mechanistic bases for tumorigenesis and the application of such knowledge to the development of rational therapeutics for cancer. The hope would be that such research would not only advance the understanding and treatment of pediatric malignancies, where I have already completed my clinical fellowship, but also be of utility in oncology in general. For the immediate future, the Howard Temin Award would greatly assist my transition to full independence as a molecular cancer scientist by providing support for the next 1-2 years of continued research under the mentorship of Dr. David Livingston. At that point, I would plan to undertake a transition to a fully independent position. Environment: The Dana-Farber Cancer Institute and Harvard Medical School provide excellent collaborative environments for the completion of the research and training goals outlined in this proposal, both during the mentored and unmentored phases of the grant. There is ready access to state- of-the-art equipment, facilities, and core services both at the DFCI and HMS. Dr. Livingston is widely regarded as an excellent scientific mentor, and his laboratory provides a wholly supportive and stimulating intellectual and scientific environment. Research: The specific aims of this proposal are: 1. Determine the mechanism whereby disruption of hypoxia-inducible transcription leads to an anti-tumor effect. 2. Search for small molecules that specifically perturb hypoxia- responsive transcription. 3. Attempt to create a mechanism-based imaging method for studying the effect of hypoxia-response inhibitors in animal tumors.